Abstract

Background

Substantial advances have been generated in understanding the pathogenesis of rheumatoid
arthritis (RA). Current murine models of RA-like disease have provided great insights
into the molecular mechanism of inflammatory arthritis due to the use of genetically
deficient or transgenic mice. However, these studies are limited by differences that
exist between human and murine immune systems. Thus, the development of an animal
model that utilizes human immune cells, will afford the opportunity to study their
function in the initiation and propagation of inflammatory arthritis.

Methods

One to two-day old irradiated NOD-scid IL2rγnull (NSG) mice were reconstituted with human CD34+ cord blood stem cells. Leukocytes
were analyzed by flow cytometry and circulating antibodies were determined by ELISA.
Arthritis was induced by injecting complete Freund’s adjuvant into knee or ankle joints.
Mice were also treated with the TNF inhibitor, Etanercept, or PBS and joints were
analyzed histologically.

Results

Humanized mice were established with high reconstitution rates and were able to spontaneously
produce human immunoglobulins as well as specific IgG in response to immunization.
Intraperitoneal injection of thioglycolate or injection of complete Freund’s adjuvant
into joints resulted in migration of human immune cells to the injected sites. Arthritic
humanized mice treated with Etanercept had markedly less inflammation, which was associated
with decreased total numbers of human CD45+ cells, including human lymphocytes and
neutrophils.

Conclusions

The humanized mouse model is a new model to study inflammatory arthritis disease using
human leukocytes without rejection of engrafted tissue. Future studies may adapt this
system to incorporate RA patient cord blood and develop a chimeric animal model of
inflammatory arthritis using genetically predisposed immune cells.